Physiological and x-ray studies of potential antisickling agents

Several aromatic compounds have been found to inhibit the gelling of sickle cell hemoglobin. We have tried to correlate the antigelling activity of such compounds with the stereo-chemistry of their binding sites in the hemoglobin molecule. This approach led to the discovery that two known antilipoproteinemia drugs, clofibrate and gemfibrozil, have antigelling activity. X-ray analysis showed that three pairs of molecules of clofibric acid, the active metabolite of clofibrate, bound to the walls of the internal cavity of deoxyhemoglobin A; only one pair bound to a quite different site, between helices A, E, and H of the alpha chains of carbon monoxide hemoglobin A. Unlike other antigelling agents, clofibric acid and related compounds decrease rather than increase the oxygen affinity of hemoglobin.